Summary: Researchers discovered a mechanism linking high sugar consumption to an increased risk of Alzheimer’s disease. The study found elevated blood glucose and increased sugar intake can lead to the proliferation of amyloid plaques in the brain – a characteristic sign of Alzheimer’s.
The study also revealed the role of neuronal ATP-sensitive potassium channels, or KATP channels, in this process. Manipulation of these channels could offer a potential new therapeutic avenue for Alzheimer’s.
- Elevated blood sugar and higher sugar intake are found to promote the buildup of amyloid plaques in the brain, increasing the risk of Alzheimer’s.
- The research team identified ATP-sensitive potassium channels (KATP channels) on neurons that link metabolic changes to amyloid-beta production in the brain.
- Potential therapeutic benefits could arise from the pharmacological manipulation of these KATP channels in diabetic and pre-diabetic patients.
Source: Wake Forest University
It’s well-known that people with Type 2 diabetes are at an increased risk of developing Alzheimer’s disease, but the reason why isn’t fully understood and is an area of current research.
Now, scientists at Wake Forest University School of Medicine have uncovered a novel mechanism that shows increased sugar intake and elevations in blood glucose are sufficient to cause amyloid plaque buildup in the brain, which increases the risk of Alzheimer’s disease. Amyloid plaque is made up of toxic proteins in the brain.
The study findings appear online in JCI Insight.
“We wanted a better understanding of the metabolic changes in diabetes that puts the brain at risk for Alzheimer’s disease or accelerates the pathology already forming in the brain of individuals who will go on to an Alzheimer’s disease diagnosis,” said Shannon Macauley, Ph.D., associate professor of physiology and pharmacology at Wake Forest University School of Medicine and principal investigator of the study.
Using a mouse model, the research team demonstrated that more amyloid plaques form when sugar water is given instead of regular drinking water. They also found that elevations in blood sugar increase the production of amyloid-beta in the brain.
“This finding is significant because it demonstrates that consuming too much sugar is enough to cause amyloid plaque proliferation and increase the risk of Alzheimer’s disease,” Macauley said.
To better understand the molecular drivers of this phenomenon, the research team identified a metabolic sensor on neurons that link changes in metabolism with neuronal firing and amyloid-beta production.
The sensors are known as adenosine triphosphate (ATP)-sensitive potassium channels or KATP channels. ATP is an energy source that all living cells need to survive.
These channels sense how much energy is available for healthy function. Disrupting these sensors changes how the brain works normally.
“Using genetic techniques in mice, we removed these sensors from the brain and showed that elevation in blood sugar no longer increased amyloid-beta levels or amyloid plaque formation,” Macauley said.
Next, researchers explored the expression of these metabolic sensors in the human Alzheimer’s disease brain and again found that the expression of these channels changes with an Alzheimer’s disease diagnosis.
According to Macauley, the study suggests that these metabolic sensors may play a role in the development of Alzheimer’s disease and could ultimately lead to new treatments.
“What’s most notable is that pharmacological manipulation of these KATP channels may hold a therapeutic benefit in reducing amyloid-beta pathology for diabetic and prediabetic patients,” said Macauley.
About this Alzheimer’s disease research news
Original Research: Open access.
“KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology” by Shannon Macauley, et al. JCI Insight
KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology
Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD).
Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis.
First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice.
Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2–/– mouse).
Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release.
These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.